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Acod1 expression in cancer cells promotes immune evasion through the generation of inhibitory peptides

James H Schofield1, Joseph Longo2, Ryan D Sheldon3

  • 1Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556, USA.

Cell Reports
|March 23, 2024
PubMed

Insights

Cancer cells resistant to PD-1 therapy produce itaconate via Acod1, inhibiting T-cell growth. Reducing Acod1 sensitizes tumors to PD-1 therapy by blocking inhibitory peptides.

Area of Science:

  • Immunology
  • Oncology
  • Metabolism

Background:

  • Immune checkpoint blockade (ICB) targeting programmed cell death protein 1 (PD-1) is a key cancer therapy.
  • Tumor microenvironment immunosuppression, driven by metabolites, limits ICB efficacy in many cancers.

Purpose of the Study:

  • Investigate the role of itaconate (ITA) and aconitate decarboxylase (Acod1) in resistance to PD-1 blockade.
  • Elucidate the mechanism by which Acod1 contributes to immunosuppression in the tumor microenvironment.

Main Methods:

  • Analysis of Acod1 and ITA levels in alphaPD-1-resistant cancer cells.
  • Genetic manipulation of Acod1 expression in cancer cells.
  • Assessment of CD8+ T-cell proliferation and function in co-culture systems.

Main Results:

  • AlphaPD-1-resistant cancer cells exhibit elevated Acod1, leading to high ITA production.
  • Decreasing Acod1 levels in resistant cells restores sensitivity to alphaPD-1 therapy.
  • Cancer cells with high Acod1 suppress naive CD8+ T-cell proliferation via secreted inhibitory peptides, not ITA.

Conclusions:

  • Acod1 is a critical mediator of resistance to PD-1 blockade in cancer.
  • Targeting Acod1 activity may overcome immunosuppression and sensitize tumors to ICB therapy.
  • Inhibitory peptides, rather than ITA, mediate Acod1-dependent CD8+ T-cell suppression.
Keywords:
Acod1CP: CancerCP: ImmunologyTCA cycleimmune evasionitaconate

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